Zika virus (ZIKV) is responsible for a massive pandemic that is associated with several devastating neuropathologic conditions, including birth defects and Guillain-Barr syndrome. There is an urgent need to understand the pathogenesis of ZIKV infections of the central nervous system (CNS) so that vaccines and therapeutics can be developed to combat ZIKV- induced CNS disease. In this application in vivo and ex vivo models of ZIKV-induced CNS pathogenesis, that have been developed in our laboratory, will be used to identify mechanisms of ZIKV CNS pathogenesis and evaluate potential therapeutic strategies for treating ZIKV- induced CNS disease. Experiments performed in Specific Aim 1 will identify ZIKV-induced CNS responses in neonatal mice and ex vivo brain slice cultures (BSCs) using an innovative genomic and bioinformatics approach, as well as by investigating the expression of specific genes and proteins and the infection and/or activation of individual CNS types. Host responses likely play a role in ZIKV-induced CNS pathogenesis and characterization and manipulation of these responses is expected to provide novel therapeutic targets for ZIKV-induced CNS disease. These therapeutic targets will be evaluated in Specific Aim 2 by determining their effect on pathogenic markers, including viral titer, cell death, tissue injury and survival. The efficacy of repurposed drugs as treatments for ZIKV-induced CNS disease will also be determined in Specific Aim 2.